Efficacy and safety of circular incision endoscopic mucosal resection and endoscopic mucosal dissection in the treatment of rectal neuroendocrine tumors：A Meta analysis

DOI: https://doi.org/10.21203/rs.3.rs-1601301/v1

Abstract

Background: circular endoincision endoscopic mucosal resection (EMR-C) and endoscopic mucosal daresection (ESD) is two common methods in the resection of the turine rectal neuroendocrine tumors. Because there is no clear consensus on the best endoscopic resection technology, we conducted a meta-analysis to compare the effectiveness and safety of ESD and EMR-C in the treatment of rectal neuroendocrine tumors.

Methods: Pubmed, EMBASE, Cochrane Library and Web of science were screened until November 2021. In the pairwise meta-analysis, according to the tumor size, 7 kinds of literature were divided into tumor size < 10mm group and tumor size 10-16mm group for subgroup analysis, and the heterogeneity between each group was analyzed.random effect and fixed-effect models were used for analysis, and sensitivity analysis and bias tests were also carried out.

Results: seven studies involving 340 cases of rectal neuroendocrine tumors. For tumors, less than 10mm, the overall resection and complete resection rate of ESD are equivalent to that of EMR-C. The incidence of intraoperative bleeding and postoperative complications are not significantly different, but ESD will take more operation time than EMR-C. For 10-16mm tumors, the overall resection and complete resection rate of ESD are significantly higher than that of EMR-C. The incidences of intraoperative bleeding were not significantly different, but ESD took more operation time than EMR-C.

Conclusion: This study shows that ESD is more effective in the treatment of rectal neuroendocrine tumors larger than 10mm because ESD has a deeper and higher mucosal resection rate. For tumors of less than 10mm, the results of EMR-C were equivalent to those of ESD

Introduction

Gastrointestinal neuroendocrine tumor is a low-grade tumor that originates from the endocrine cells of the gastrointestinal tract and other organs and is the second most common malignant tumor of the digestive system. Among gastrointestinal neuroendocrine tumors, the small intestine has the highest incidence, with approximately 2.8-8 cases per 1 million per year. [1]The incidence of the rectum is 13.7%, which is higher than that of the colon at 7.8%[2].

Epidemiological reports point out that the incidence rate in Asian countries is much higher than that in European and American countries[3]. An American epidemiological study shows that rectal neuroendocrine tumors (rectal NETs) in the United States are more likely to occur in white and African Americans, and are different from those in Asian populations. Therefore, there are ethnic differences in rectal NETs[4]. Research on rare cancers in Asian countries also concludes inequality in tumor sites and gender differences between European and American countries [5]. In recent years, it has been discovered that with the development of endoscopy and the diagnosis of rectal NETs, the incidence has increased year by year[6, 7].

Rectal neuroendocrine tumors are rare tumors. [8] Because of its good differentiation, and good prognosis, natural survival time is longer[9]. At present, due to the development of new endoscopy technology and the occurrence and development of endoscopic sonography (EUS), submucosal dissection (ESD) and other operations, the assessment is more accurate and the resection is more complete. Therefore, when treating rectal neuroendocrine tumors, the endoscopy Mirror method is the preferred treatment[10]. In 2015, the European neuroendocrine Oncology Association agreed that endoscopic therapy is a feasible treatment for tumors less than 2cm, but the premise is that the tumor is well- differentiated and there is no lymptasth node measis or invasion of muscle tissue[11]. At present, the commonly used endoscopic methods are endoscopic submucosal resection (ESD), endoscopic resection (EMR) and modified endoscopic mucosal resection (m-emr). The modified endoscopic mucosal resection includes: ligation device emr-b, transparent cap device EMR-C, dual-channel endoscope emr-d, ligation device emr-l and circumferential sion EMR (clemr). The transparent cap device (EMR-C) in improved endoscopic mucosal resection uses a transparent cap to suck and cut off the submucosa. This technology is an improved EMR technology. Cutting the submucosa from the muscular propria can ensure the safe edge of the tumor and solve the insecurity of incomplete resection of EMR technology[12]. Since Inoue et al first reported the use of EMR-C in 1993[13], EMR-C was applied in the treatment of gastrointestinal submucosal tumors gradually. Endoscopic submucosal dissection (ESD) , which originated in Asian countries, is a replacement for early gastric cancer resection [14], especially for colorectal cancer with early invasive cancer. ESD uses a submucosal injection to peel the submucosal plane, which can completely remove the pathological tissues. Compared with EMR, ESD has a higher histological resection rate[15],But at the same time, ESD requires higher professional knowledge and  shows more adverse events(such as perforation and bleeding)[16] . However, there is no consensus on which method can better deal with rectal tumors. The choice of endoscopic rectal resection technique depends on tumor size, mucosal and submucosal appearance[17]. ESD in colorectal lesions is more difficult than in gastric lesions due to its location and anatomy[18]. The improved EMR-C makes up for the poor resection rate of traditional surgery and takes less time than ESD. At the same time, it uses cap-assisted adsorption to treat tumor lesions. Because its material is plastic, it can be soft or hard,  it is beneficial to pass through the stenosis. The site, suitable for lesions in the colorectal region[19] .However, compared with ESD, EMR-C is less used clinically and lacks clinical evidence support. The safety and effectiveness of EMR-C still needs to be further evaluated. Therefore, in this meta-analysis, our purpose is to explore the effectiveness and safety of ESD and EMR-C in the successful treatment of rectal neuroendocrine tumors.

1. Data And Methods

1.1 Search strategy

search Pubmed, EMBASE, Cochrane Library, web of science and other databases from the establishment of the database to November 22, 2021. The search words are: " endoscopic mucosal research ", “endoscopic Submucosal Dissection “, “submucosal dissection, endoscopic”, " neuroendocrine tumors " , "surgical procedure, endoscopic "and "surgical procedures". We identified papers that studied the efficacy of EMR-C and ESD in the treatment of rectal carcinoid and conducted secondary screening according to the inclusion and exclusion criteria.

1.2 Method

1.2.1 Literature inclusion and exclusion criteria:

Inclusion criteria: (1) subjects: Patients with rectal neuroendocrine tumors confirmed by pathological results; (2) intervention measures: comparative study of EMR-C and ESD; (3) OUTCOME MEASURES: at least 2 or more outcome measures was included in the article: operation time, overall resection rate, complications, metastasis or recurrence. Exclusion criteria: (1) review, meta-analysis, review and conference articles; (2) relevant literature on the required outcome indicators was not provided; (3) there was no complete article.

1.2.2 Data extraction:

two researchers independently read the title and abstract of the literature, determined the literature according to the inclusion and exclusion criteria, then read the full-text literature that meets the criteria and evaluate literature. In case of any disagreement, seek mutual agreement between the three authors.

1.3 Statistical methods:

Use stata15.1 Software for statistical analysis. According to the tumor size, 7 kinds of literature were divided into tumor size < 10mm group and tumor size 10-16mm group for subgroup analysis, and the heterogeneity between each group was analyzed. If there was no significant heterogeneity (P ≥ 0.05, I2 ≤ 50%), the fixed-effect model was used for meta-analysis; If there is heterogeneity (P < 0.05, I2 > 50%), the random effect model will be used for analysis. Differences between ESD and EMR were compared using a pairwise meta-analysis, with risk ratios (RR) and standardized mean difference estimated (SMD) for dichotomous and continuous variables respectively. We further analyzed all outcomes  to determine if there is any significant differences between the two treatment options ESD and EMR via sensitivity analysis. Finally, the restricted maximum likelihood model with the Kapp variance estimator was used to identify potential sources of heterogeneity via meta-regression.  Newcastle Ottawa scale was used for quality assessment of non-randomized cohort studies20. Standardized means difference (SMD) and 95% CI was used for continuous variables, and relative risk (RR, odd ratio, or) and 95% CI was used for binary variables. P < 0.05 was statistically significant.

2. Results

2.1 Literature retrieval results and quality evaluation of included studies

2.1.1 The basic situation of the included literature: 

a total of 1364kind of literature was retrieved, 350 duplicate kind of literature was excluded, and 1,007kind of literature was removed according to the inclusion and exclusion criteria, of which 728 were comparative studies of non-EMR-C and ESD treatments. 228 were other tumors, 25 were literature reviews and systematic reviews, 3 were conference articles, 2 were reader responses, and 13 were incomplete articles. Finally, 7 related articles were included, 7 of which were retrospective studies.

Table 1 

Basic information of the article

2.1.2. Quality evaluation included

The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies.  The total score of NOS is 9, the total score of the paper is a, and ≥ 6 cases are classified as methodological reasonable research. The total evaluation scores of 7 articles are between 7-9, which shows that the quality of 7 literature is relatively high (see Figure2) 

Table 2

Document quality evaluation chart 

study

selection

comparability

outcome

total

 

 

REC

SNEC

AE

DO

SC 

AF

AO 

FU

AFU

 

Zhi-Feng Zhao 

1

1

1

1

1

0

1

0

0

6

 

Kazuhiro Toriyama

1

1

1

1

0

0

1

0

1

6

 

Dong-Hoon Yang

1

1

1

1

0

1

1

0

1

7

 

Ding-Guo Zhang

1

1

1

1

1

0

1

1

1

8

 

Xianfei Wang 

1

1

1

1

1

0

1

0

1

7

 

Ru Chen

1

1

1

1

1

0

1

1

1

8

 

Jinyan Zhang

1

1

1

1

0

1

1

0

1

7

 

REC: representativeness of the exposed cohort; SNEC: selection of the non-exposed cohort; AE: ascertainment of exposure; DO:demonstration that out come of interest was not present at start of study; SC: study controls for tumor size; AF: study controls for any additional factors; AO: assessment of outcome;FU: follow-up long enough for outcomes to occur; AFU: adequacy of follow-up of cohorts. “1” means that the study is satisfied the item and “0” means the opposite situation

 

 

 

 

2.2. 1.  Operation time: 

6 out of 7 articles dealt with operative time,therefore, six kinds of literature are included for statistical analysis. Therefore, subgroup analysis is carried out according to the tumor size. The results show that the operation time of the EMR-C group is shorter than that of ESD in the comparison between tumors less than 10mm, The difference was statistically significant (SMD = -4.41, 95% CI = -7.52-1.30, P = 0.005); compared with tumors of 10-16mm, the operation time of EMR-C group was shorter than that of ESD, and the difference was statistically significant (SMD = -2.41, 95% CI = -4.04-0.77, P = 0.004 see Figure2 ).

2.2.2 Overall tumor resection: 

7 kinds of literature involved overall resection, including 3 articles in the < 10mm group. The overall resection rate of the two surgical methods was 100%, which had no comparative significance, so 4 articles were included for analysis. According to the tumor size, the literature was divided into two groups for subgroup analysis. The results showed that there was no significant difference in the overall resection effect of tumors with a diameter less than 10mm between the EMR-C and ESD groups, The difference was not statistically significant (RR = 1.10, 95% CI = 0.93-1.31, P = 0.247); the overall resection rate of tumors with a diameter range of 10-16mm in ESD operation was significantly higher than that in EMR-C operation (RR = 0.93, 95% CI = 0.87-0.99, P = 0.03). (see Figure 3)

2.2.3 Intraoperative bleeding : 

Six pieces of literature involved intraoperative bleeding, including one in the < 10mm group and two in the 10-16mm group. The number of intraoperative bleeding in the two surgical methods was 0, which had no comparative significance. Therefore, three  pieces of literature were included for analysis. According to the tumor size, the   pieces of literature were divided into two groups for subgroup analysis. The results showed that there was no significant difference in intraoperative bleeding between EMR-C and ESD groups, The difference was not statistically significant (RR = 0.51, 95% CI = 0.15-1.78, P = 0.294). The analysis results of the group with tumor sizes of 10-16mm showed that there was no significant difference between EMR-C and ESD in intraoperative bleeding of tumors with a diameter of 10-16mm (RR = 0.42, 95% CI = 0.08-2.15, P = 0.300). (see . Figure 4) 

2.2.4 Complete resection of tumor:

Six pieces of literature related to tissue resection, so six pieces of literature was included for analysis. According to the tumor size, the literature was divided into two groups for subgroup analysis. The analysis results showed that there was no significant difference in the complete resection effect of tumors with a diameter less than 10mm between the EMR-C and ESD groups, The difference was not statistically significant (RR=0.98,95%CI=0.88-1.10,P=0.784); the analysis of the results of the group with tumor size of 10-16mm showed that the complete resection rate of tumors with a diameter range of 10-16mm by ESD was significantly higher than that by EMR-C (RR=0.82，95%CI=0.74-0.98,P=0.000). (see Figure 5)

2.2.5 Postoperative bleeding:

All 7kinds of literature involved the amount of postoperative bleeding, including 2kinds of literature in the < 10mm group. The number of postoperative bleeding cases in the two surgical methods was 0, which had no comparative significance. Therefore, 5 kinds of literature were included for analysis. According to the tumor size, the literature was divided into two groups for subgroup analysis. The results showed that there was no significant difference in postoperative bleeding between the EMR-C group and the ESD group, The difference was not statistically significant (RR = 3.06, 95% CI = 0.54-17.30, P = 0.205); the analysis results of the fixed model with the size of 10-16mm showed that there was no significant difference in postoperative bleeding between EMR-C and ESD groups (RR = 0.32, 95% CI = 0.05-1.95, P = 0.215). (see Figure 6)

2.2.6 Publication bias:  

publication bias analysis was conducted for each result. Except for the operation time, the funnel diagram of each result showed a symmetrical distribution. The P values of begger test and egger test were > 0.05, indicating that there was no publication bias. The funnel plot distribution of operation time was asymmetric, and the begger test p < 0.05 and egger test p < 0.05 suggested that there was publication bias.

3. Discussion

Neuroendocrine tumors (NETs) are low-grade and nonfunctional heterogeneous tumors, which is characterized by relatively slow growth and long patient survival time[20]. Gastric and rectal neuroendocrine tumors are less likely to metastasize, but they will develop rapidly once they metastasize[21]. Surgical intervention is the standard method of treatment. In this study, a total of 7 literature involving 340 patients were included. They were divided into two groups: less than 10mm and 10-16mm according to the tumor size. All the included patients were confirmed as rectal neuroendocrine tumors by endoscopy and histological examination, without lymph node or other organ metastasis and carcinoid syndrome.

The meta-analysis showed that the complete resection rate and total resection rate of ESD in tumors with a diameter of 10-16 mm was higher than those in the EMR-C group, but there was no significant difference between the two groups in the complete resection and total resection of tumors with a diameter of less than 10 mm, which was comparable to Hai-. The results are consistent with a meta-analysis by Ping Zhang et al. And at the same time this study makes up for the lack of analysis results of the study's lack of complete resection rate of 10-16mm tumors. The complete resection rate and the overall resection rate are  important indicators for judging tumor treatment technology. ESD originated from the resection of gastric cancer, using various endoscopic tools to remove the lesions on the submucosal plane, because ESD can determine the edge of the tumor, and then remove the tumor. Therefore, in comparison, ESD helps to remove larger tumors in the rectum more completely..[22] . In smaller tumors, both EMR-C and ESD can show a good resection effect [23].

 Meta-analysis shows that the ESD procedure takes longer than the EMR-C procedure. Because ESD endoscopic resection first requires a mixed solution injection, the mucosa is cut after the tumor is relieved, and a circular cut around the lesion is performed with an electrosurgical knife. Finally, the lesion is separated from the underlying muscle membrane by a pressurized water jet or some injection or cutting tools [24]. Compared with EMR-C using the auxiliary cap to remove after suction, the ESD procedure is more complicated, requires more tools and equipment, and has higher technical requirements for doctors. Studies have shown that there is a negative correlation between ESD operation time and doctors’ skills, and doctors with higher skills have shorter operation times.[25]. However, due to its complicated operating procedures, excluding its doctor's skills and intraoperative complications, the average time of ESD surgery is still higher than that of EMR-C. 

In this study, we found that there is no significant difference between the two treatment groups of EMR-C and ESD. Bleeding and perforation are the main complications of endoscopic resection. Bleeding is divided into intraoperative and postoperative bleeding. Studies have shown that bleeding and perforation are the main complications of ESD. The reasons for this result are as follows: rectal neuroendocrine tumors have no invasive metastasis at the time of diagnosis, and the resection area is relatively small; the typical endoscopic features of rectal neuroendocrine tumors are small and smooth sessile lesions with chromaffin granular nodules in the mucosa and the mucosal surface There is no obvious deformation, and the rectal wall is thickened[17]; the rectum is fixed behind the peritoneum, so the endoscope is easy to operate in the rectum, and the intraoperative damage is small. 

Six of the seven kinds of literature suggested that the recurrence and metastasis after endoscopic treatment of rectal carcinoid were 0, and only one suggested that there was a recurrence rate of 20% after ESD resection of  10-16mm tumors. Therefore, in the meta-analysis, the incidence of recurrence and metastasis after operation in the two groups was not statistically analyzed. The number of recurrence and metastasis after the two types of surgery is small, which may lead to the following results: first, the follow-up time is short. Seven kinds of literature take 3 / 6 / 12 months as the follow-up time, but the follow-up length is within two years. The 5-year survival rate of rectal carcinoid from 1993 to 2004 is 74% - 88%, which is the highest among all gastrointestinal and pancreatic nets, This is because the tumor diameter of the vast majority of rectal carcinoids is less than 1cm and limited to the submucosa. Only a part of the tumor size is greater than 2cm, and cancer invades the muscularis propria[26]. Therefore, the follow-up time of two years is not enough to explain the effectiveness of ESD and EMR-C treatment. Second, rectal neurodocenrine tumors are well-differentiated,nearly 0.5% of malignant diseases[27] , and the incidence of recurrence and metastasis is low[28] . The above reasons can explain the low incidence of recurrence and metastasis of rectal nets after endoscopic surgery in the two groups.

The results of sensitivity analysis show that our results are statistically trustworthy, but our study also has some limitations. Firstly, all the included articles are small sample retrospective studies, the research quality is relatively low, and there are few studies included. The next research will increase the number of studies. Second, the subjects of all the included articles were Asians. There were differences between Asians and European and American countries in the predilection site, predilection population, clinical stage and histological stage. Therefore, the inclusion of only Asian populations may have an impact on the results of the study. Third, the postoperative follow-up time is short, resulting in postoperative recurrence and metastasis, which may affect the results. Fourth, there are few studies on the results of hospitalization time and hospitalization expenses, which may have an impact on the safety of endoscopic treatment. Advantages of our research: first, previous studies have mostly focused on the comparison between improved traditional endoscopic resection and endoscopic resection, and the comparison between endoscopic mucosal dissection and endoscopic resection. Previous studies have confirmed that traditional endoscopic resection has the important deficiency of a low resection rate, so this kind of research is not in line with the current clinical situation. In this study, EMR-C in modified endoscopic resection was compared with ESD to find the best evidence of endoscopic technology for the treatment of rectal neuroendocrine tumors. Second, according to the fact that tumor size is an important factor affecting the choice of operation, recurrence and metastasis, all outcome indicators are classified according to tumor size,  to prevent tumor size from becoming a bias factor and provide more accurate evidence for the selection of correct endoscopic surgery.

In the publication bias test, there was a publication bias in the operation time, and the reasons were analyzed as follows: the first tumor size factor; the second doctor's technical difference; the third: the number of included articles was too small. We grouped the articles into groups of less than 10 mm and greater than 10 mm according to tumor size, and then conducted a publication bias analysis again. The results showed that there was no publication bias, and the analysis of tumor size may be an important factor affecting the bias. Since too large tumors can increase the difficulty of resection of lesions, CETINSAYA B [25] et al. pointed out that the surgeon's technical level and the difficulty of specific lesions are factors affecting the operation time, which can explain the occurrence of publication bias in the results.

In conclusion, this meta-analysis shows that ESD and EMR-C have good effects on rectal tumors less than 10mm, and both have good safety and effectiveness; For tumors with a diameter less than 10mm with good pathological differentiation and no metastasis and recurrence, EMR-C should be selected as the preferred treatment scheme. The reasons are that EMR-C has a  short operation time, low technical requirements for doctors, simple operation degree and may reduce hospitalization expenses. As for the research on the effectiveness of tumor treatment, postoperative prognosis depends on tumor size, aggressiveness, metastatic disease, and stage[29]. Among them, the occurrence of metastasis and recurrence after treatment is a key indicator.. Some studies have shown that tumors > 10mm are one of the important risk factors for predicting metastasis [30]. The corresponding metastasis rates of rectal neuroendocrine tumors with tumor diameters < 10mm, 10-20mm and > 20mm were 3%, 66% and 73% respectively [31] IT can be seen that for tumors > 10mm, more effective and better resection methods should be selected to prevent metastasis and recurrence. This can explain the results of this study in 10-16mm rectal tumors: ESD treatment is better than EMR-C treatment, the overall resection rate and complete resection rate is significantly higher than EMR-C group, the treatment effectiveness is significantly higher than EMR-C group, and there is no significant difference in the safety of the two groups. However, the following meta-analysis should include studies with follow-up time > 5 years, populations in European and American countries, randomized controlled trials of ESD and EMR-C, and relevant studies on hospital stay and cost to confirm the above findings.

Declarations

I declare that the authors have no competing interests as defined by Springer, or other interests that might be perceived to influence the results and/or discussion reported in this paper. 

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